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METABOLISM OF LIPIDS:
temperature extremes
(1) They are stored in an anhydrous form (2) Their fatty acids are more reduced than monosaccharides.
1 g of triacylglycerols stores more than six times as much energy as a 1 g of glycogen Glycogen reserves are depleted in 12 to 24 hours after eating, triacylglycerols within several weeks. Fat breakdown about 50 % of energy in liver, kidney and skeletal muscles up to 95 % of energy cardiac muscle
Fats are the major source of energy for: fasting animal organism in diabetes
Fatty acids and glycerol substances that are directly used as a fuel by mammalian organisms.
Fatty acids (FA) and glycerol for metabolic fuels are obtained from triacylglycerols: (1) In the diet
Bile salts are amphipathic, they act as detergent emulsifying the lipid drops and increasing the surface area of the interface.
Lysophosphoglycerides are absorbed and in the intestinal cells are reesterified back to glycerophospholipids.
Lysophosphoglycerides can act as detergent and therefore in high concentration can disrupt cellular membranes. Lysophosphoglyceride is normally present in cells in low concentration.
Snake venom contain phospholipase A2 and causes the lysis of erythrocytes membranes.
Dietary cholesterol
Most dietary cholesterol is unesterified
Cholesteryl esters are hydrolyzed in the intestine by an intestinal esterase Free cholesterol is solublized by bile-salt micelles for absorption After absorption in the intestinal cells cholesterol react with acyl-CoA to form cholesteryl ester.
Micelles migrate to the microvilli and lipids diffuse into the cells. Bile acids are actively absorbed and transferred to the liver via portal vein.
Bile salts can circulate through intestine and liver several time per day.
In the intestinal cells the fatty acids are converted to fatty acyl CoA molecules. Three of these molecules can combine with glycerol, or two with monoacylglycerol, to form a triacylglycerols.
O CH2 OH O OH O O C R2 + R1 CO SCoA CH2 CH CH2 O O OH O R1 R2 + R3 CO SCoA CH2 CH CH2 O O O C O C O C R1 R2 + HSCoA R3 C O C R1 R2 + HSCoA
1.
CH CH2
2.
CH2 CH CH2
O O OH
C O C
1-st reaction is catalyzed by monoacylglycerol acyltransferase 2-nd reaction is catalyzed by diacylglycerol acyltransferase
TGs, cholesterol and cholesterol esters are insoluble in water and cannot be transported in blood or lymph as free molecules
These lipids assemble with phospholipids and apoproteins (apolipoproteins) to form spherical particles called
lipoprotein
Structure: Hydrophobic core: -TGs, -cholesteryl esters Hydrophilic surfaces: -cholesterol, -phospholipids, -apolipoproteins
Chylomicrons
are the largest lipoproteins (180 to 500 nm in diameter)
are synthesized in the ER of intestinal cells contain 85 % of TGs (it is the main transport form of dietary TGs). apoprotein B-48 (apo B-48) is the main protein component
deliver TGs from the intestine (via lymph and blood) to tissues (muscle for energy, adipose for storage).
bind to membrane-bound lipoprotein lipase (at adipose tissue and muscle), where the triacylglycerols are again degraded into free fatty acids and monoacylglycerol for transport into the tissue are present in blood only after feeding
exocytosis
Lymphatic vessel
VLDL
contain 50 % of TGs and 22 % of cholesterol two lipoproteins apo B-100 and apo E the main transport form of TGs synthesized in the organism (liver)
deliver the TGs from liver to peripheral tissue (muscle for energy, adipose for storage)
bind to membrane-bound lipoprotein lipases (triacylglycerols are again degraded into free fatty acids and monoacylglycerol)
Apo B
Apo E cholesterol phospholipids
Formed free fatty acids and glycerol pass into the cells
Chylomicrons and VLDL which gave up TGs are called remnants of chylomicrons and remnants of VLDL
Remnants are rich in cholesterol esters Remnants of chylomicrons are captured by liver Remnants of VLDL are also called intermediate density lipoproteins (IDL) Fate of the IDL: - some are taken by the liver - others are degraded to the low density lipoproteins (LDL) (by the removal of more triacylglycerol)
LDL
LDL are formed in the blood from IDL and in liver from IDL (enzyme liver lipase) LDL are enriched in cholesterol and cholesteryl esters (contain about 50 % of cholesterol) Protein component - apo B-100
Receptors for LDL are localized in specialized regions called coated pits, which contain a specialized protein called clathrin
Apo B-100 on the surface of an LDL binds to the receptor Receptor-LDL complex enters the cell by endocytosis. Endocytic vesicle is formed
Feedback regulation: abundance of intracellular cholesterol suppresses the synthesis of LDL receptors and so the uptake of additional cholesterol from plasma LDL is blocked
Familial hypercholesterolemia
congenital disease when LDL receptor are not synthesized (mutation at a single autosomal locus) the concentration of cholesterol in blood markedly increases severe atherosclerosis is developed (deposition of cholesterol in arteries)
xanthomas
HDL
acyltransferase in
HDL esterifies cholesterols, convert it to cholesterol esters and transport to the liver
High serum levels of cholesterol cause disease and death by contributing to development of atherosclerosis Cholesterol which is present in the form of the LDL is so-called "bad cholesterol."
Cholesterol in the form of HDL is referred to as "good cholesterol HDL functions as a shuttle that moves cholesterol throughout the body
LDL/HDL Ratio
The ratio of cholesterol in the form of LDL to that in the form of HDL can be used to evaluate susceptibility to the development of atherosclerosis
adipocyte
At low carbohydrate and insulin concentrations (during fasting), TG hydrolysis is stimulated by epinephrine, norepinephrine, glucagon, and adrenocorticotropic
hormone.
Lipolysis - hydrolysis of triacylglycerols by lipases. A hormone-sensitive lipase converts TGs to free fatty acids and monoacylglycerol Monoacylglycerol is hydrolyzed to fatty acid and glycerol or by a hormone-sensitive lipase or by more specific and more active monoacylglycerol
lipase
Oxidation of Glycerol
Glycerol is absorbed by the liver. Steps: phosphorylation, oxidation and isomerisation.
Isomerase
Fatty acids are converted to CoA thioesters by acyl-CoA synthetase (ATP dependent) The PPi released is hydrolyzed by a pyrophosphatase to 2 Pi
Two phosphoanhydride bonds (two ATP equivalents) are consumed to activate one fatty acid to a thioester
translocase.
The acyl group is transferred back to CoA (enzyme carnitine acyltransferase II).
1. Oxidation of acyl CoA by an acyl CoA dehydrogenase to give an enoyl CoA Coenzyme - FAD
2. Hydration of the double bond between C-2 and C-3 by enoyl CoA hydratase with the 3-hydroxyacyl CoA (b-hydroxyacyl CoA) formation
4. Cleavage of 3-ketoacyl CoA by the thiol group of a second molecule of CoA with the formation of acetyl CoA and an acyl CoA shortened by two carbon atoms.
Enzyme b-ketothiolase.
The shortened acyl CoA then undergoes another cycle of oxidation The number of cycles: n/2-1, where n the number of carbon atoms
One round of b oxidation: 4 enzyme steps produce acetyl CoA from fatty acyl CoA
Each round generates one molecule each of: FADH2 NADH Acetyl CoA Fatty acyl CoA (2 carbons shorter each round)
Fates of the products of b-oxidation: - NADH and FADH2 - are used in ETC
- acetyl CoA - enters the citric acid cycle - acyl CoA undergoes the next cycle of oxidation
The balanced equation for oxidizing one palmitoyl CoA by seven cycles of b oxidation ATP generated
1. Propionyl CoA is carboxylated to yield the D isomer of methylmalonyl CoA. The hydrolysis of an ATP is required. Enzyme: propionyl CoA carboxylase Coenzyme: biotin
2. The D isomer of methylmalonyl CoA is racemized to the L isomer Enzyme: methylmalonyl-CoA racemase
Acyl CoA dehydrogenase transfers electrons to O2 to yield H2O2 instead of capturing the highenergy electrons by ETC, as occurs in mitochondrial boxidation.
A carboxybiotin intermediate is formed. ATP is hydrolyzed. The CO2 group in carboxybiotin is transferred to acetyl CoA to form malonyl CoA. Acetyl CoA carboxylase is the regulatory enzyme.
During the fatty acid synthesis all intermediates are linked to the protein called acyl carrier protein (ACP-SH), which is the component of fatty acyl synthase complex.
The pantothenic acid is a component of ACP. Intermediates in the biosynthetic pathway are attached to the sulfhydryl terminus of phosphopantotheine group.
The elongation phase of fatty acid synthesis starts with the formation of acetyl ACP and malonyl ACP.
Condensation reaction. Acetyl ACP and malonyl ACP react to form acetoacetyl ACP. Enzyme -
Reduction.
ACP reductase
Dehydration.
Reduction. The final step in the cycle reduces crotonyl ACP to butyryl ACP. NADPH is reductant. Enzyme - enoyl ACP
reductase.
In the second round butyryl ACP condenses with malonyl ACP to form a C6-b-ketoacyl ACP. Reduction, dehydration, and a second reduction convert the C6-bketoacyl ACP into a C6acyl ACP, which is ready for a third round of elongation.
Overall reaction of palmitate synthesis from acetyl CoA and malonyl CoA
Acetyl CoA carboxylase plays an essential role in regulating fatty acid synthesis and degradation.
The carboxylase is controlled by hormones: glucagon, epinephrine, and insulin.
Global Regulation
Insulin stimulates fatty acid synthesis causing dephosphorylation of carboxylase. Glucagon and epinephrine have the reverse effect (keep the carboxylase in the inactive phosphorylated state). Protein kinase is
Carboxylase is
Local Regulation
Acetyl CoA carboxylase is allosterically stimulated by
citrate. The level of citrate is high when both acetyl CoA and ATP are abundant (isocitrate dehydrogenase is inhibited by ATP). Palmitoyl CoA inhibits carboxylase.
Fed state:
Response to Diet
carnitine acyltransferase I
Starvation:
Epinephrine and glucagon are produced and stimulate adipose cell lipase and the level of free fatty acids rises
Inactivate carboxylase, so decrease formation of malonyl CoA (lead to increased transport of FA into mitochondria and activate the b-oxidation pathway)
Formation of phosphatidate
Two separate acyl transferases (AT) catalyze the acylation of glycerol 3-phosphate. The first AT (esterification at C1) has preference for saturated fatty acids; the second AT (esterification at C2) prefers unsaturated fatty acids.
Phosphatidic acid (phosphatidate) is an common intermediate in the synthesis of TGs and GPLs
Phosphatidate can be converted to two precursors: - diacylglycerol (precursor for TGs and neutral phospholipids) - cytidine diphosphodiacylglycerol (CDPdiacylglycerol) (precursor for acidic phospholipids)
Triacylglycerol
Phosphatidylethanolamine Phosphatidylcholine
Synthesis of TGs
Diacylglycerol can be acylated to triacylglycerol (in adipose tissue and liver) Enzyme:
acyltransferase
phosphatidylethanolamine
Phosphatidylinositol can be converted to phosphatidylinositol 4,5-biphosphate which is the precursor of the second messenger inositol 1,4,5-triphosphate